In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction action between a neurotransmitter and a surface receptor. Neurotransmitters, such as L-glutamate and L-aspartate, are released by the sending neurons and travel across the synapse where they interact with the surface receptor of the receiving neuron. Such neurotransmitters are referred to as excitatory amino acids (EAA's) because they mediate the major excitatory pathways in the CNS. Likewise, the surface receptors that respond to EAA's are generally referred to as EAA receptors.
EAA receptors are of two principle classes; the "lionotropic" receptors which are directly coupled to the cell membrane adjacent to the cation channel openings; and the "metabotropic" receptors which are G-proteins coupled to multiple second messenger systems which produce enhanced phosphoinositide (PI) hydrolysis, activation of phospholipase D, changes in cAMP formation and changes in ion channel function.
Ionotropic receptors are subclassed into at least three major groups, based upon their sensitivity to a selective agonist. The three major groups are generally referred to as the N-methyl-D aspartate (NMDA) group; the .alpha.-amino-3-hydroxy-5-methyl-isoxazole-4 propionic acid (AMPA) group; and the kainic acid (KA) group.
EAA's and their receptors play an important role in a variety of physiological processes, such as long-term potentiation (LTP), synaptic plasticity, motor control, respiration, cardiovascular regulation and sensory perception.
Excessive or inappropriate stimulation of EAA receptors generally leads to neuronal cell damage or cell death by excitotoxicity. Excitotoxicity has been suggested as the major cause of neuronal degeneration in a number of CNS diseases and conditions, such as Alzheimer's Disease, Huntington's Chorea, amyotrophic lateral sclerosis (ALS), cerebral ischemia and many other related neurodegenerative diseases.
It has been suggested that the blocking actions of antagonist compounds can abate the cell death caused by excitotoxicity. Selective antagonists which block the action of certain types or subtypes of EAA receptors have been synthesized and tested in the part, particularly at the NMDA receptors. Prior examples of NMDA selective antagonists are described and claimed in U.S. Pat. No. 4,968,678 issued Nov. 6, 1990 and U.S. Pat. No. 5,284,957, issued Feb. 8, 1994. Selective antagonists could be particularly useful in individuals who demonstrate receptor selective excitotoxicity.